Kirsch’s response expectancy theory is based on the idea that what people experience depends partly on what they expect to experience.[5] According to Kirsch, this is the process that lies behind the placebo effect and hypnosis. The theory is supported by research showing that both subjective and physiological responses can be altered by changing people’s expectancies.[6] The theory has been applied to understanding pain, depression, anxiety disorders, asthma, addictions, and psychogenic illnesses.

Kirsch’s analysis of the effectiveness of antidepressants was an outgrowth of his interest in the placebo effect. His studies in this area are primarily meta-analyses, in which the results of previously conducted clinical trials are aggregated and analyzed statistically. His first meta-analysis was aimed at assessing the size of the placebo effect in the treatment of depression.[7] The results not only showed a sizable placebo effect, but also indicated that the drug effect was surprisingly small. This led Kirsch to shift his interest to evaluating the antidepressant drug effect. Kirsch’s first meta-analysis was limited to published clinical trials. The controversy surrounding this analysis led him to obtain files from the U.S. Food and Drug Administration (FDA) containing data from trials that had not been published, as well as those data from published trials. Kirsch’s analyses of the FDA data showed that the difference between antidepressant drugs and placebos was not clinically significant, according to the criteria used by the National Institute for Health and Clinical Excellence (NICE), which establishes treatment guidelines for the National Health Service (NHS) in the United Kingdom.[8] Kirsch challenges the chemical-imbalance theory of depression, writing "It now seems beyond question that the traditional account of depression as a chemical imbalance in the brain is simply wrong." [9] In 2014, in the British Psychological Society's Research Digest, Christian Jarrett included Kirsch's 2008 antidepressant placebo effect study in a list of the 10 most controversial psychology studies ever published.[10]

Kirsch has focused some of his research on the topic of hypnosis. The basis of his hypnosis theory is that placebo effects and hypnosis share a common mechanism: response expectancy. Kirsch's idea on this topic is that the effects of both hypnosis and placebos are based upon the beliefs of the participant.[11] He has characterized clinical hypnosis as a "nondeceptive placebo."[12]